EP4285895A1 - Forme posologique orale de nitrofurantoïne - Google Patents

Forme posologique orale de nitrofurantoïne Download PDF

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Publication number
EP4285895A1
EP4285895A1 EP22177334.4A EP22177334A EP4285895A1 EP 4285895 A1 EP4285895 A1 EP 4285895A1 EP 22177334 A EP22177334 A EP 22177334A EP 4285895 A1 EP4285895 A1 EP 4285895A1
Authority
EP
European Patent Office
Prior art keywords
nitrofurantoin
tablets
blend
immediate release
dosage form
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP22177334.4A
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German (de)
English (en)
Inventor
Faysal Kalmoua
Martina Feitzinger
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Adalvo Ltd
Original Assignee
Adalvo Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Adalvo Ltd filed Critical Adalvo Ltd
Priority to EP22177334.4A priority Critical patent/EP4285895A1/fr
Publication of EP4285895A1 publication Critical patent/EP4285895A1/fr
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4816—Wall or shell material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4816—Wall or shell material
    • A61K9/4825—Proteins, e.g. gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds

Definitions

  • the present invention relates to a pharmaceutical capsule formulation containing Nitrofurantoin immediate release blend and extended-release tablets.
  • Nitrofurantoin is an antibacterial agent specific for urinary tract infections.
  • the brand product Macrobid ® is a hard gelatin capsule containing an equivalent of 100 mg of nitrofurantoin composed of 25 mg of nitrofurantoin macrocrystals and 75 mg of nitrofurantoin monohydrate in the form of a powder blend.
  • nitrofurantoin 1-[[[5-nitro-2-furanyl]methylene]amino]-2,4-imidazolidinedione.
  • the chemical structure is the following:
  • nitrofurantoin monohydrate 1-[[[5-nitro-2-furanyl]methylene]amino]-2,4-imidazolidinedione monohydrate.
  • the chemical structure is the following:
  • nitrofurantoin has slower dissolution and absorption than nitrofurantoin monohydrate.
  • Nitrofurantoin monohydrate in the form of a powder blend upon exposure to gastric and intestinal fluids, forms a gel matrix that releases nitrofurantoin over time. Nitrofurantoin monohydrate is very slightly soluble in water.
  • EP250023 and EP250038 describe a pharmaceutical capsule formulation containing Nitrofurantoin for oral administration comprising a particulate mixture in a capsule shell which is soluble in gastrointestinal juice, and wherein the first layer contains nitrofurantoin monohydrate in the form of a sustained release particulate mixture, and the second layer contains macrocrystalline nitrofurantoin in the form of a rapid release particulate mixture.
  • a preferred process for producing the sustained release pharmaceutical capsules comprises the steps of: (1) preparing the particulate mixture, and (2) filling the particulate mixture into a capsule shell.
  • the present invention relates to an oral dosage form which is a sustained-release pharmaceutical capsule formulation containing a combination of immediate release and sustained-release Nitrofurantoin.
  • the oral dosage form which is a sustained release capsule contains:
  • the immediate release part is in the form of a powder blend containing macrocrystalline Nitrofurantoin and one or more pharmaceutically acceptable excipients selected from the group of a filler, a glidant and a first diluent, and optionally a disintegrant.
  • the glidant is preferably selected from a group of talc, silica, magnesium carbonate, silicon dioxide.
  • a particularly preferred glidant for the immediate release part is talc.
  • the filler is preferably selected from a group of corn starch, microcrystalline cellulose, mannitol, calcium phosphate.
  • a particularly preferred filler is corn starch.
  • the disintegrant is preferably selected from a group of crospovidone, croscarmellose sodium, sodium starch glycolate, cross-linked alginic acid.
  • the first diluent is preferably selected from a group of lactose, dextrose, calcium phosphate, mannitol, starch, sorbitol, sucrose.
  • a particularly preferred diluent for the immediate release part is lactose monohydrate or lactose.
  • the immediate release part contains macrocrystalline nitrofurantoin, corn starch, talc and lactose monohydrate.
  • the immediate release part is prepared by blending the active substance with the one or more pharmaceutically acceptable excipients.
  • the sustained release part is in the form of tablets containing Nitrofurantoin monohydrate, a release modifier and one or more additional pharmaceutically acceptable excipients selected from the group of a release modifier, a binder, a second diluent, a glidant and a lubricant.
  • the largest dimension of tablets is up to 7 mm, preferably within the range of 4.5-6.5 mm.
  • the tablets might be cylindrical, with a diameter of 4.5-6.5 mm and height of 2.5-3.5 mm.
  • the release modifier is preferably selected from a group of polymers like carbomer homopolymer, pectin, hydroxypropyl methylcellulose (HPMC), polyethylene glycol, polyethylene oxide.
  • a particularly preferred release modifier is carbomer homopolymer (e.g., Carbopol 971-P, an acrylic acid crosslinked with allyl sucrose or allyl pentaerythritol).
  • the binder is preferably selected from a group of polyvinylpyrrolidone, starch, pregelatinized starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC).
  • a particularly preferred binder is polyvinylpyrrolidone (povidone).
  • the second diluent is preferably selected from a group of powdered sugars like confectioners' sugar, lactose, mannitol, microcrystalline cellulose.
  • a particuarly preferred second diluent for the sustaned release part is confectioners' sugar.
  • the glidant is preferably selected from a group of talc, silica, magnesium carbonate, silicon dioxide.
  • a particularly preferred glidant is talc.
  • the lubricant is magnesium stearate.
  • the sustained release tablets contain Nitrofurantoin Monohydrate, carbomer homopolymer, polyvinylpyrrolidone, confectioners' sugar, talc and magnesium stearate.
  • Tablets are prepared by wet granulation process using a granulation liquid based on water, ethanol and/or a mixture thereof.
  • the granulation liquid is a solution of the binder in a mixture of water and ethanol, wherein preferably the ratio of water and ethanol is 80: 20 w/w.
  • the oral dosage form according to the invention contains:
  • the oral dosage form according to the invention contains
  • the immediate release blend and the sustained release tablets are combined in the ratio corresponding to the amount of the immediate release blend equivalent to 1 weight part of Nitrofurantoin and the amount of the sustained release tablets equivalent to 3 weight parts of Nitrofurantoin.
  • the immediate release blend and the sustained release tablets are combined in the ratio corresponding to the amount of the immediate release blend equivalent to 25 mg of Nitrofurantoin and the amount of the sustained release minitablets equivalent to 75 mg of Nitrofurantoin.
  • the oral dosage form according to the invention contains:
  • the oral dosage form according to the invention contains
  • the oral dosage form contains a. an immediate release blend containing Ingredients mg % w/w Nitrofurantoin Macrocrsytals, USP 25.00 19.841 Talc, USP (Imperial 1885L) 11.50 9.127 Corn Starch, NF (UNI-Pure ® F) 16.00 12.698 Lactose Monohydrate, NF (Pharma 100M) 73.50 58.334 126.00 100.000 b.
  • sustained release tablets containing Ingredients mg/unit (tablet) % W/W Nitrofurantoin Monohydrate, USP 40.35 45.593 Carbomer Homopolymer NF, (Type A) (Carbopol 971-P) 3.38 3.814 Povidone USP/NF (Plasdone K-29/32) 24.00 27.119 Confectioners' Sugar USP/NF 17.28 19.520 Purified Water, USP q.s q.s Dehydrated Alcohol, USP q.s q.s Talc USP (Imperial 1885L) 1.75 1.977 Magnesium Stearate, NF 1.75 1.977 88.5 100.000 wherein two tablets are combined with the immediate release blend corresponding to 25 mg of nitrofurantoin.
  • sustained release tablets and an immediate release powder blend are filled into capsule (preferably a hard gelatine capsule or HPMC capsule).
  • the capsules according to the present invention are capsules having a shell which is soluble in gastrointestinal juice.
  • the capsules according to the present invention comprise hard gelatin capsules and HPMC capsules.
  • the preferred capsules are hard gelatin capsules which are soluble in gastric juice.
  • the matrix structure and shape of the oral dosage form play a critical role in having better control on the release rate of active substance from the extended-release matrix.
  • the structure and shape of a gel matrix produced from a powder varies when it gets in contact with intestinal fluids, and a plug of powder mass usually does not have a defined structure. Therefore, the release of the active substance from such matrix over a period of time shows high variation.
  • the matrix in tablets is formed through well-defined parameters followed during manufacturing.
  • the matrix structure of the tablets is reproducible, the shape thereof is defined, and therefore, the release of drug substance is more consistent in the release profiles as evident by lower RSD (Relative Standard Deviation) from the tablet formulation than the powder formulation.
  • RSD Relative Standard Deviation
  • Sustained-release tablets have the following advantages: improved content uniformity, consistent and reproducible dissolution rate, and improved product stability.
  • the variation in the weight of the mass in tablets is lower than the blend, when filled in the capsule form.
  • the immediate release powder blend containing Nitrofurantoin Macrocrystals is prepared using the following procedure:
  • Capsules containing 100 mg of Nitrofurantoin in form of Nitrofurantoin Monohydrate and Nitrofurantoin Macrocrystals are as follows: Item Material Description mg/capsule 1 Nitrofurantoin Monohydrate Tablets, 37.5 mg (sustained release tablets) 2 x 88.5 mg (2 Tablets) 2 Nitrofurantoin Macrocrystals Final Blend, 25 mg (immediate release blend) 126 3 Hard Gelatin Capsules, Size 1 Coni-Snap White Cap / White Opaque Body 76 (1 cap) Total Net Weight 303 Total Weight of Filled Capsule 379
  • the reference product Macrobid ® and the sustained release capsules according to the invention were tested for dissolution according to the below method.
  • Dissulution procedure in different media Dissolution media 0.01 N HCl Buffer pH 4.5 Buffer pH 7.5 All specification time points in 900 mL of 0.01 N HCl 900 mL of 0.01 N HCl solution [5.1.2.1] added. After 1 hour time point 50 mL of Acetate Buffer Concentrate [5.1.2.5] added and continued to remaining time points with pH 4.5 dissolution medium 900 mL of 0.01 N HCl solution [5.1.2.1] added.
EP22177334.4A 2022-06-03 2022-06-03 Forme posologique orale de nitrofurantoïne Pending EP4285895A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP22177334.4A EP4285895A1 (fr) 2022-06-03 2022-06-03 Forme posologique orale de nitrofurantoïne

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
EP22177334.4A EP4285895A1 (fr) 2022-06-03 2022-06-03 Forme posologique orale de nitrofurantoïne

Publications (1)

Publication Number Publication Date
EP4285895A1 true EP4285895A1 (fr) 2023-12-06

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EP22177334.4A Pending EP4285895A1 (fr) 2022-06-03 2022-06-03 Forme posologique orale de nitrofurantoïne

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0250038A2 (fr) 1986-06-16 1987-12-23 Norwich Eaton Pharmaceuticals, Inc. Capsule à libération retardée
EP0250023A1 (fr) 1986-06-16 1987-12-23 Norwich Eaton Pharmaceuticals, Inc. Forme de dosage de la nitrofurantoine
US4777033A (en) * 1985-06-11 1988-10-11 Teijin Limited Oral sustained release pharmaceutical preparation
US20050202079A1 (en) * 2004-03-15 2005-09-15 Mylan Pharmaceuticals Inc. Novel orally administrable formulation of nitrofurantoin and a method for preparing said formulation
US20060002997A1 (en) * 2002-08-23 2006-01-05 Puneet Shamar Nitrofurantoin controlled release dosage form

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4777033A (en) * 1985-06-11 1988-10-11 Teijin Limited Oral sustained release pharmaceutical preparation
EP0250038A2 (fr) 1986-06-16 1987-12-23 Norwich Eaton Pharmaceuticals, Inc. Capsule à libération retardée
EP0250023A1 (fr) 1986-06-16 1987-12-23 Norwich Eaton Pharmaceuticals, Inc. Forme de dosage de la nitrofurantoine
US4772473A (en) * 1986-06-16 1988-09-20 Norwich Eaton Pharmaceuticals, Inc. Nitrofurantoin dosage form
US20060002997A1 (en) * 2002-08-23 2006-01-05 Puneet Shamar Nitrofurantoin controlled release dosage form
US20050202079A1 (en) * 2004-03-15 2005-09-15 Mylan Pharmaceuticals Inc. Novel orally administrable formulation of nitrofurantoin and a method for preparing said formulation

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